Histone deacetylase inhibitors modulates the induction and expression of amphetamine-induced behavioral sensitization partially through an associated learning of the environment in mice

Abstract

The behavioral sensitization produced by repeated amphetamine treatment may represent the neural adaptations underlying some of the features of psychosis and addiction in humans. Chromatin modification (specifically histone hyperacetylation) was recently recognized as an important regulator of psychostimulant-induced plasticity. We have investigated the effects of treatment with the histone deacetylase (HDAC) inhibitors butyric acid (BA, 630 mg/kg, i.p) and valproic acid (VPA, 175 mg/kg, i.p.) on the psyhcostimulant locomotor sensitization induced by amphetamine (AMPH, 2.0 mg/kg, i.p.). Neither BA nor VPA had locomotor effects alone, but both significantly potentiated the amphetamine-induced behavioral sensitization in mice. At the molecular level, VPA and amphetamine produced an increase of histone H4 acetylation in the striatum as detected by Western blot analysis, while co-treatment with VPA and AMPH produced an additive effect on histone H4 acetylation. We then administered the HDAC inhibitors after treatment with amphetamine for 8 days to establish locomotor sensitization. We found that repeated administration of VPA or BA for 6 days inhibited the expression of sensitized response following amphetamine challenge. Finally, in a context-specific model we studied the effect of HDAC inhibitors on amphetamine-induced association of the treatment environment (associative learning). We found that VPA and BA enhance the context-specificity of expression of amphetamine sensitization. Thus, HDAC inhibitors differentially modulate the induction and expression of amphetamine-induced effects. Together, these results suggest that dynamic changes in chromatin modification may be an important mechanism underlying amphetamine-induced neuronal plasticity and associative learning.

Selective Boosting of Transcriptional and Behavioral Responses to Drugs of Abuse by Histone Deacetylase Inhibition

“…Conversely, acetylation-related processes seem less relevant in the development of drug tolerance and dependence (as measured by the intensity of drug withdrawal), which result from transient homeostatic adaptations occurring within the cells and circuits directly stimulated by each drug and are not considered core symptoms of addiction (Hyman et al, 2006). This view is in agreement with earlier pharmacological and genetic studies on psychostimulants-induced sensitization and CPP (Bilbao et al, 2008;Kalda et al, 2007;Kumar et al, 2005;Levine et al, 2005;Renthal et al, 2007), as well as with the few preceding studies indicating that HDACis do not facilitate the development of tolerance (Wang et al, 2007) and that histone acetylation might be more involved in the expression than in the induction of drug dependence (Pandey et al, 2008). Future studies should further explore this intriguing dissociation.…”

“…Recent studies have provided initial support to this hypothesis. For example, the administration of psychostimulants, such as cocaine, at dosages that promote conditioned place preference (CPP) or locomotor sensitization results in histone hyperacetylation at specific loci relevant to the development of addictive behavior (Kumar et al, 2005;Levine et al, 2005;Renthal et al, 2008aRenthal et al, , 2007 and perhaps also at the bulk chromatin level (Kalda et al, 2007). Furthermore, genetic studies have established a functional role for histone acetyltransferase (HAT) (Levine et al, 2005) and histone deacetylase (HDAC) activities in the mechanisms of action of psychostimulants, a view also supported by pharmacological experiments with HDAC inhibitors (HDACi) (Kalda et al, 2007;Kumar et al, 2005;Renthal et al, 2007).…”

Using iPSC‐derived human DA neurons from opioid‐dependent subjects to study dopamine dynamics

“…A preclinical study has shown that multiple injections of VPA when delivered consecutively after methamphetamine could reduce the addictive behavior in rodents (Kalda et al. 2007). Consistently, clinical studies suggest that cocaine craving and abuse are diminished by treating cocaine abusers with valproate (Halikas et al.…”

Morphine-induced synaptic plasticity in the VTA is reversed by HDAC inhibition

“…Acute and chronic administration of psychostimulants and morphine elicits histone modifications such as histone acetylation at a specific subset of learningassociated genes in the brain reward circuitry including the VTA that could facilitate and consolidate lasting neural and behavioral plasticity induced by drug abuse. Moreover, increasing histone acetylation through pre-or coadministration of histone deacetylase (HDAC) inhibitors (HDACis) in conjunction with abused drugs promotes or opposes drug-induced synaptic and behavioral abnormalities, suggesting that this epigenetic mark might be required to potentiate or prevent an addicted state (Jing et al 2011;Kalda et al 2007; Kennedy et al 2013;Kumar et al 2005;Levine et al 2005;Renthal et al 2007Renthal et al , 2009Sanchis-Segura et al 2009;Sun et al 2012;Wang et al 2010). This opens the possibility of targeting epigenetic mechanisms during initial learning or memory retrieval of drug-associated cues as a novel pharmacological therapy for extinction of drug-seeking behaviors.…”